Beta cells - transplantation and regenerative medicine
The overall aim of the research group is to develop means to intervene with the development of type 1 diabetes mellitus and find treatment strategies to restore glucose homeostasis in patients with type 1 diabetes mellitus using cell therapy.
The dual role of Professor Per-Ola Carlsson as experimental and clinical scientist simplifies translational approaches, and the research group is active both at the Department of Medical Sciences and the Department of Medical Cell Biology. Studies are conducted to elucidate the importance of islet endothelial, neural, stromal or their progenitor cells for beta-cell regeneration and function, and to investigate the concept of islet heterogeneity. Other studies investigate the adaptation of pancreatic islets to the implantation organ, i.e. the so called engraftment process, following transplantation, and develop bioengineering strategies (coating of islets with supporting stem cells, oxygen carriers and growth factors, as well as with use of scaffolds) to improve results of pancreatic islet transplantation by enhancement of engraftment e.g. by improved revascularization. Human islets are tested in these experimental systems with a focus to produce clinically applicable protocols.
We also perform research to develop safe and effective means to generate new human beta-cells by stimulating adult beta-cell proliferation, e.g. by stem cell stimulation, or by stem cell differentiation in vivo. Clinical studies are performed to prevent development of type 1 diabetes in patients, e.g. by autologous mesenchymal stem cell transplantation, and to develop means for beta-cell imaging by positron emission tomography. We also conduct studies to improve the results of clinical islet transplantation, e.g. by encapsulation in order to avoid immune suppression of the patients.
Heterogeneity of pancreatic islets in health and disease
Sara Ullsten, Joey Lau, Per-Ola Carlsson
We have identified a functional reserve of islet endocrine cells in rodents. Normally 20-25% of islets are low oxygenated and with low protein biosynthesis, but these cells may be activated upon need during increased functional demands. On the other hand, more islets become down-regulated when beta-cell mass is increased. We have also observed that the most blood perfused islets, having a higher vascular density, have a superior beta-cell function, proliferation and gene expression. Noteworthy, these islets also seem more prone to develop amyloid deposits, more prone to cellular death when stressed by hypoxia or cytokines and are the first affected by disease at development of type 1 diabetes.
Communication between endothelial or neural cells and beta-cells
Liza Grapensparr, Joey Lau, Carl-Johan Drott, Monica Sanberg, Per-Ola Carlsson
We have observed an importance for endothelial-beta-cell communication to maintain beta-cell proliferation, differentiation and function. In other experiments, the possibility for endothelial progenitor cells, neural crest stem cells and Schwann cells to stimulate human beta-cell proliferation and function have been investigated. We have established techniques to bioengineer islet surfaces with neural crest stem cells and endothelial progenitor cells and to in this manner improve human islet vascularization, beta-cell survival and proliferation after transplantation. Parenterally administered mesenchymal stem cells and neural crest stem cells home to damaged endogenous islets in mice, repair (mesenchymal stem cells) and induce regeneration (neural crest stem cells) in the damaged pancreatic tissue with substantial regrowth of insulin-producing cells.
Intervention strategies to preserve residual beta-cell mass in newly developed type 1 diabetes
Daniel Espes, José Caballero, Louise Magnusson, Per-Ola Carlsson
Possibilities to save residual beta-cell mass in newly diagnosed patients with type 1 diabetes by autologous transplantation with mesenchymal stem cells are tested in investigator-initiated studies. In a first phase 1/2a trial, we observed no adverse events of the procedure and preserved residual insulin production for at least a year. These individuals are now followed up to five years after diagnosis to investigate if the effect is sustained and the immunological changes to a Th2 phenotype persistent. We have also initiated a larger (national), blinded, phase 2 efficacy trial with the same concept. New techniques to visualise beta-cell mass are in parallel developed by positron emission technology using the PET ligand [11C]-5-hydroxy-tryptophane.
Encapsulation of pancreatic islets for clinical transplantation
Daniel Espes, Per-Ola Carlsson
Clinical islet transplantation is hampered by the need of chronic immune suppression of the recipients. In a collaborative effort with Beta-O2, a newly developed oxygenized chamber to harbour the human islets is tested in an ongoing investigator-initiated phase 1/2a trial in type 1 diabetes patients. The macrodevice protects the islets from immune rejection, whereas oxygen is supplied daily into a refillable oxygen tank. A follow up study is also planned with instead transplantation of human embryonic stem cells derived to insulin producing cells within the same device.